DESIGN AND DEVELOPMENT OF POTENTIAL ANTISICKLING AGENTS

这项研究计划的总体目标是延长我们的血红蛋白 研究和关注基于结构的药物发现：a)结构- 作为抗脑缺血药物的功能研究和变构效应 B)设计和开发抗粘连/抗凝胶剂。 因此，我们的具体目标包括：(1)设计和合成 进一步建立结构特征的血红蛋白变构效应器 在调节变构的蛋白质中，可以发展为 潜在的抗缺血药物；(2)氧平衡和动力学 反应变构效应的分析；(3)X射线结晶学 HBA-变构效应器的结构测定和精制 提供与a)氨基运动有关的信息的络合物 变构转变中的酸；b)水在变构转变中的作用 变构探针的结合；以及c)氨基的鉴定 酸残基是调节变构的关键 平衡；(4)合理设计和合成新的立体专一性 暂时性共价抗感冒剂，将特异性结合到 HBS聚合中的靶残基；(5)X-射线 测定HBA-结合部位的结晶学研究 效应器复合体。这些将提供必要的原子细节 合理重新设计分子，提高其功效；(6) 合成的抗恶心、抗凝血分子的评价 以及变构效应的各种方法的活性。

The overall goal of this research program is to extend our hemoglobin studies and focus on structure based drug discovery in: a) Structure- Function studies and allosteric effectors as Anti-ischemic Agents and b) Design and Development of Antisickling/Antigelling Agents. Therefore our specific aims include: (1) Design and synthesis of hemoglobin allosteric effectors to further establish structural features within the protein that regulate allostery and can be developed as potential anti-ischemic agents; (2) Oxygen equilibrium and kinetic analyses of the reacted allosteric effectors; (3) X-ray crystallographic structure determination and refinement of HbA-allosteric effector complexes to provide information pertaining to a) the movements of amino acids during the allosteric transition; b) the role of water in the binding of the allosteric probes; and c) the identification of amino acid residues that are key to the regulation of the allosteric equilibrium; (4) rational design and synthesis of new stereospecific transient covalent antisickling agents that will specifically bind to target residues involved in the polymerization of HbS; (5) X-ray crystallographical studies to determine the binding sites of HbA- effector complexes. These will provide the atomic details necessary for rational re-design of molecules to increase their efficacy; (6) Evaluation of the synthesized molecules for antisickling, antigelling and allosteric effector activity by various methods.